PROJECT SUMMARY/ABSTRACT Su H. Chu, PhD, MS is a biostatistician and molecular epidemiologist with strong and substantial commitments to integrative omic research in respiratory and neurodevelopmental disease. Her career objective is to become an independent investigator with expertise in developing and applying novel statistical methods and multiomic network approaches that facilitate mechanistic understanding of the intersection of respiratory and neurodevelopmental disease. This proposal combines Dr. Chu?s extensive training in integrative omic methods development, along with her experience in genetic and metabolomic research, to examine the integrative metabolomic etiology of asthma and attention-deficit/hyperactivity disorder overlap (AAO). A wealth of epidemiological literature has revealed with remarkable consistency that asthmatic patients are at greater risk for ADHD, and vice versa, with a number of longitudinal studies of childhood asthma indicating excess risk of ADHD in adolescence and adulthood. However, no studies have directly interrogated the biological mechanisms by which these conditions may be related. The central hypothesis of this proposal is that childhood asthma and ADHD share both common and distinct dysregulated metabolic processes, some of which may have drivers that are genetic in origin. This will be explored using existing genetic and metabolomic data from the Childhood Asthma Management Program (CAMP), the Vitamin D Antenatal Asthma Reduction Trial (VDAART), and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC), three large prospective cohorts of children with extensive longitudinal phenotyping and multiple omic data types, by identifying metabolites and metabolic profiles associated with AAO (aim 1), constructing multiomic models and features that characterize dysregulated metabolic processes and their upstream drivers in AAO (aim 2), and validation and replication of all findings (aim 3). As Dr. Chu completes these aims, her career development program will facilitate the achievement of her primary training goals: 1) increase clinical understanding of ADHD and asthma diagnosis and treatment; 2) gain a nuanced understanding of best methods for, and practical experience in, the biological and statistical integration of genetic and metabolomic data; 3) develop skills in machine learning and integrative network methods for multiomic analysis; 4) strengthen current areas of experience to stay on the cutting edge of new analytic and study design techniques; and 5) enhance skills in mentorship, teaching, and the responsible conduct and communication of research. The support of a diverse mentoring team comprised of world experts in the fields of asthma and psychiatric genetics, metabolomics, integrative omics, and statistics, along with her strong quantitative training and the vibrant intellectual community of Harvard Medical School and the Brigham and Women?s Hospital, ensure the success of this proposal. Finally, this research will use state-of-the-art multiomic techniques to lay the initial groundwork for understanding the pathobiology of asthma and ADHD comorbidity, a major and well-established public health concern, from which new research programs will emerge.